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Pretargeted Radioimmunotherapy Based on the Inverse Electron Demand Diels-Alder Reaction
Published on: January 29, 2019
Immune Checkpoint Blockade Enhances the Abscopal Effect of [177Lu]Lu-DOTA-JR11 PRRT in an SSTR2-Heterogeneous
Zhaoting Cheng1, Huimin Zhou1, Luoxia Liu1
1Department of Nuclear Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Disease; National Center for Major Public Health Events, 1095 Jiefang Ave, Wuhan, Hubei, 430030, China.
Purpose:
The overexpression of somatostatin receptor (SSTR) in neuroendocrine neoplasms (NENs) provides a molecular basis for treatment with peptide receptor radionuclide therapy (PRRT). However, heterogeneous SSTR expression limits therapeutic efficacy. Immune checkpoint inhibitors (ICIs) enhance the abscopal effect of external radiotherapy. This study investigated whether combining PRRT using the SSTR antagonist [177Lu]Lu-DOTA-JR11 with anti-PD-L1 monoclonal antibody (mAb) therapy could enhance the abscopal effect in an SSTR2-heterogeneous bilateral tumor model.
Methods:
A bilateral SSTR2-heterogeneous murine melanoma model was established by contralateral implantation of B16F10-SSTR2 and B16F10-wildtype tumors. Mice received saline, PRRT, anti-PD-L1 mAb, or combination therapy. Tumor growth, survival, PET/CT imaging, histopathology, immune profiling (including PD-L1 expression, CD45+ cells, CD8+ cells, myeloid-derived suppressor cells [MDSCs], and macrophage phenotypes), and serum cytokine levels were assessed to evaluate local and systemic antitumor responses.
Results:
PRRT monotherapy selectively inhibited SSTR2-positive tumors but showed minimal efficacy against SSTR2-negative tumors. Combination therapy significantly suppressed the growth of both tumors, prolonged survival, and reduced [18F]FDG uptake in tumors. These effects were accompanied by increased Granzyme B expression, enhanced CD8+ cell infiltration, expansion of M1 macrophages and effector memory T cells, and reductions in MDSCs and M2 macrophages. Serum IFN-γ and IL-2 levels were significantly elevated, indicating robust systemic immune activation.
Conclusion:
PRRT combined with PD-L1 blockade remodels the tumor immune microenvironment, elicits potent systemic antitumor immunity, and enhances the abscopal effect in SSTR2-heterogeneous tumors. This strategy may help address target-expression heterogeneity in radionuclide therapy.
Insights
Combining peptide receptor radionuclide therapy (PRRT) with PD-L1 blockade enhances abscopal effects in heterogeneous tumors. This combination therapy remodels the tumor immune microenvironment, activating systemic antitumor immunity.
Area of Science:
- Oncology
- Immunotherapy
- Radiopharmaceuticals
Background:
- Neuroendocrine neoplasms (NENs) overexpress somatostatin receptors (SSTRs), enabling peptide receptor radionuclide therapy (PRRT).
- Therapeutic efficacy of PRRT is limited by heterogeneous SSTR expression.
- Immune checkpoint inhibitors (ICIs) can augment radiotherapy's abscopal effect.
Purpose of the Study:
- To investigate if combining PRRT with an SSTR antagonist ([177Lu]Lu-DOTA-JR11) and anti-PD-L1 monoclonal antibody (mAb) therapy enhances the abscopal effect.
- To evaluate the combination therapy's efficacy in a bilateral SSTR2-heterogeneous tumor model.
Main Methods:
- Established a bilateral SSTR2-heterogeneous murine melanoma model using B16F10-SSTR2 and B16F10-wildtype tumors.
- Administered saline, PRRT, anti-PD-L1 mAb, or combination therapy to mice.
- Assessed tumor growth, survival, PET/CT imaging, histopathology, immune profiling, and serum cytokine levels.
Main Results:
- PRRT monotherapy showed limited efficacy against SSTR2-negative tumors.
- Combination therapy significantly suppressed growth of both tumor types and prolonged survival.
- Combination therapy induced systemic immune activation, evidenced by increased CD8+ T cells, M1 macrophages, and elevated serum IFN-γ and IL-2 levels.
Conclusions:
- PRRT combined with PD-L1 blockade remodels the tumor immune microenvironment, promoting systemic antitumor immunity.
- This combination strategy enhances the abscopal effect in SSTR2-heterogeneous tumors.
- The findings suggest a potential approach to overcome target-expression heterogeneity in radionuclide therapy.
